Functional biomarkers complementing static BRCA/HRD testing for dynamic PARP inhibitor therapy in ovarian cancer: a narrative review
- 1Department of Gynecologic Cancer, Shaanxi Provincial Cancer Hospital, Xi’an
- 2Department of Pathology, Shaanxi Provincial Cancer Hospital, Xi’an
Abstract
Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the management of high-grade serous ovarian cancer (HGSOC). Yet, current treatment decisions remain almost exclusively guided by static BRCA/homologous recombination deficiency (HRD) genotyping. This paradigm is increasingly challenged by a profound eligibility–benefit gap: real-world data show 93.4% of patients are PARPi-eligible, but only 22.0% achieve meaningful 2-year progression-free survival benefit, compounded by 10–30% HRD test failure rates, inability to capture dynamic resistance evolution, and negligible predictive value in the ~50% of HGSOC that are homologous recombination-proficient. This narrative review, based on literature up to June 2026, systematically evaluates functional biomarkers that complement BRCA/HRD testing by assessing real-time tumor biology. To our knowledge, this is the first review to integrate these biomarkers into a unified whole-disease-course framework accounting for evidence level, assay cost, and global resource setting. RAD51 immunohistochemistry directly visualizes homologous recombination repair capacity, achieving 95% accuracy in predicting PARPi response in preclinical patient-derived xenograft models and demonstrating robust predictive value in prospective clinical cohorts. The KELIM model, derived from early CA-125 kinetics and evaluated in >12,000 patients within prospective trial and registry datasets, provides a no-additional-assay-cost, tissue-independent readout of chemosensitivity with potential for broad, low-cost global deployment. Circulating tumor DNA enables noninvasive longitudinal monitoring of resistance, potentially preceding radiographic progression by weeks to months. Exploratory immune and artificial intelligence-based multimodal markers further refine response stratification. We propose deployment of these biomarkers at four critical clinical nodes—diagnosis, post-chemotherapy, maintenance, and progression—to guide therapy selection dynamically. By transitioning from static genotype-based eligibility to real-time functional phenotyping, this integrated strategy aims to close the eligibility–benefit gap and advance adaptive precision oncology for ovarian cancer globally. As a narrative review, this work aims to offer forward-looking conceptual frameworks and stimulate future research rather than to establish high-level clinical evidence or formal guidelines.
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BibTeX
@article{wu2026functional,
title = {{Functional biomarkers complementing static BRCA/HRD testing for dynamic PARP inhibitor therapy in ovarian cancer: a narrative review}},
author = {Tao Wu and Pengchuang Zhang and Ruxing Xi and Xiaowei Wang and Lijuan Hu and Yahui Shen and Kai Tao and Jianrong Lu and Guoqing Wang},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1989686},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1989686/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Functional biomarkers complementing static BRCA/HRD testing for dynamic PARP inhibitor therapy in ovarian cancer: a narrative review
AU - Tao Wu
AU - Pengchuang Zhang
AU - Ruxing Xi
AU - Xiaowei Wang
AU - Lijuan Hu
AU - Yahui Shen
AU - Kai Tao
AU - Jianrong Lu
AU - Guoqing Wang
PY - 2026
DA - 2026/10/13
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1989686
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1989686/full
AB - Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the management of high-grade serous ovarian cancer (HGSOC). Yet, current treatment decisions remain almost exclusively guided by static BRCA/homologous recombination deficiency (HRD) genotyping. This paradigm is increasingly challenged by a profound eligibility–benefit gap: real-world data show 93.4% of patients are PARPi-eligible, but only 22.0% achieve meaningful 2-year progression-free survival benefit, compounded by 10–30% HRD test failure rates, inability to capture dynamic resistance evolution, and negligible predictive value in the ~50% of HGSOC that are homologous recombination-proficient. This narrative review, based on literature up to June 2026, systematically evaluates functional biomarkers that complement BRCA/HRD testing by assessing real-time tumor biology. To our knowledge, this is the first review to integrate these biomarkers into a unified whole-disease-course framework accounting for evidence level, assay cost, and global resource setting. RAD51 immunohistochemistry directly visualizes homologous recombination repair capacity, achieving 95% accuracy in predicting PARPi response in preclinical patient-derived xenograft models and demonstrating robust predictive value in prospective clinical cohorts. The KELIM model, derived from early CA-125 kinetics and evaluated in >12,000 patients within prospective trial and registry datasets, provides a no-additional-assay-cost, tissue-independent readout of chemosensitivity with potential for broad, low-cost global deployment. Circulating tumor DNA enables noninvasive longitudinal monitoring of resistance, potentially preceding radiographic progression by weeks to months. Exploratory immune and artificial intelligence-based multimodal markers further refine response stratification. We propose deployment of these biomarkers at four critical clinical nodes—diagnosis, post-chemotherapy, maintenance, and progression—to guide therapy selection dynamically. By transitioning from static genotype-based eligibility to real-time functional phenotyping, this integrated strategy aims to close the eligibility–benefit gap and advance adaptive precision oncology for ovarian cancer globally. As a narrative review, this work aims to offer forward-looking conceptual frameworks and stimulate future research rather than to establish high-level clinical evidence or formal guidelines.
SN - 2234-943X
ER -